JP7237962B2 - Methods of treating autoimmune microvascular disorders - Google Patents

Description

FIELD OF THE INVENTION The present invention relates to the use of diosmin or diosmethine, or a pharmaceutically acceptable salt thereof, to treat autoimmune microvascular diseases and their complications, including digital ulcers in scleroderma. Regarding the method.

Background Systemic sclerosis (a/k/a scleroderma) is a classic autoimmune microvasculature disorder characterized by fibrosis and skin thickening, and multiorgan dysfunction. The disease has a global incidence of about 20 per million people per year and a prevalence of about 240-280 per million people (Mayes 2003a,b, Rosa 2011, Barnes 2012). Several forms and subsets are recognized. Diffuse systemic sclerosis affects several combinations of skin and other organ systems. Limited systemic sclerosis affects the skin, generally distal to the elbows and knees, and is associated with less visceral involvement than diffuse systemic sclerosis. Localized scleroderma is a highly localized form of systemic sclerosis of the skin that causes localized patches of thickened fibrous skin, but is usually not associated with visceral involvement. CREST syndrome (calcinosis, Raynaud's phenomenon, esophageal disorders, toe sclerosis, telangiectasia) is commonly thought to be part of diffuse systemic sclerosis, but it can also be a localized form. It may also be seen as systemic sclerosis (Hachula 2011).

Digital ischemia is a hallmark of systemic sclerosis seen in >95% of patients (McMahan 2010). Digital ulcers contribute significantly to the morbidity and compromise vitality and cost of systemic sclerosis (Hughes 2016). An observational study using data from the RUSTAR database found that the most common subtype was localized skin disease. Fifty-nine percent of patients had ≥2 ulcers, 67% had at least one hospitalization, and 57% reported significant impairment in daily activities compared with 37% of patients without ulcers (Brand 2015).

Calcium channel blockers and vasodilators are considered first-line treatments for systemic sclerosis. Bosentan, the first drug used to treat pulmonary hypertension, was approved by the European Union in 2007 for reducing the number of new digital ulcers and the progression of digital ulcer disease in patients with systemic sclerosis. approved by Iloprost is another drug used to treat pulmonary arterial hypertension (PAH), systemic sclerosis, Raynaud's phenomenon and other diseases in which blood vessels are narrowed and blood cannot flow to the tissues. Response rates are low for all of these interventions.

Factors contributing to the development of digital ulcers include taut, thin skin, repeated microtrauma, calcification, underlying microangiitis and chronic digital ischemia due to repeated bouts of Raynaud's phenomenon (Nitsche 2012). , Hughes 2016). Loss of capillaries with avascular areas seen by capillary microscopy, especially in the presence of high serum IL-6 levels, is predictive of future ulcer development (Alivernini 2009, Lambova 2011, Cutolo 2013). Digital ulcers are highly painful, slow to heal – up to 32% become chronic (Steen 2009, Doveri 2011) – and are associated with significant functional loss (Steen 1997, Khindas 2011, Berezne 2011). . Digital terminal capillary bundles or ulcers located on the extensor surfaces are thought to be due to ischemia due to a combination of microvascular disease and actual capillary loss associated with ischemia from vasospasm associated with Raynaud's phenomenon. . Ulcers located on bony prominences are more often due to tissue ischemia due to repeated microtrauma and taut fibrous skin associated with underlying microvascular disease.

Microvascular disease has been reported to be associated with the development of many clinical manifestations of systemic sclerosis (Guiducci 2007). Capillary changes in systemic sclerosis are characteristic and exacerbate with disease progression (Camargo 2015). The Capillary Microscopic Skin Ulcer Risk Index (CSURI) has been developed with sufficient predictive value for the likelihood of future ulcer development to be useful in designing aggressive preventive treatment regimens (Sebastiani 2009, Smith 2013).
People who exhibit Raynaud's features in the absence of other features of systemic rheumatic disease and who have abnormal capillary microscopic findings and one or more typical systemic sclerosis autoantibodies are considered Raynaud's patients without those findings. are 60 times more likely to develop systemic sclerosis compared to those who have it (McMahon 2010).

Diosmin is a flavonoid present at low concentrations in citrus fruits. When used commercially, it is similarly extracted from citrus fruits, but is produced by the simple oxidation of the approximating Speridine, which is present in much greater abundance than diosmine. Diosmetin is the aglycone of diosmin, a form of which is found in the blood following oral ingestion of diosmin (Cova 1992).

Diosmin has been used and approved in much of Europe and, for over 30 years, has been used under various brand names, primarily Daflon®, as a drug for the treatment of chronic venous insufficiency and its complications, including venous ulcers. ) has been sold. Hundreds of articles mostly addressed diosmin's main historical therapeutic target, the venous system, with its molecular, phlebotonic and clinical effects.

Attempts have been made to define and quantify the effects of diosmin on microvessels. Intravital microscopy was used to test the effects of diosmin in a streptozotocin-induced diabetic hamster cheek pouch model (Bouskela 1995). Pretreatment with diosmin significantly reduced the number of capillary leaks induced by each of the test articles, bradykinin and LTB4. After 30 minutes of ischemia followed by reperfusion, macromolecular permeability died, as did the number of leukocytes that adhered to the endothelium.

Diosmin has also been shown to inhibit the overexpression of endothelial cell adhesion molecules typically encountered with leukocytes in various ischemia/reperfusion models (Shields 2004, Coleridge Smith 2000b). In another study using ischemia/reperfusion followed by intravital microscopy in the hamster cheek pouch model (Bouskela 1997), untreated control animals exhibited marked arteriolar dilation, decreased blood flow velocity and functional capillaries. showed a decrease in density. Pretreatment with diosmin at doses of 2, 20, 80 and 160 mg/kg/d reversed all these changes to normal in a dose-dependent manner. In a related animal model (di Souza 2014), phlebosclerosis was induced in rabbit ear veins by injection of 5% ethanolamine oleate. Treatment with diosmin 300 mg/kg/d, started 7 days before sclerotherapy and continued for 4 days after the procedure, prevented increases in venous and arteriolar diameters and reduced the number of adherent leukocytes. , reduced the number of capillary leak sites, maintained functional capillary density, and reduced perivenous edema (p<0.001 for all parameters).

Given this background, the object of the present invention is to provide microvascular diseases, in particular autoimmune microvascular diseases, and in particular, but not exclusively, ulcers and ulcers in subjects suffering from systemic sclerosis. To develop effective treatments for systemic sclerosis, including digital ulcers.

It is another object to provide new uses of diosmin and diosmetin and their pharmaceutically acceptable salts.

The inventors have unexpectedly discovered that diosmin has the ability to treat microangiitis associated with systemic sclerosis and digital ulcers that occur in patients suffering from systemic sclerosis. Based on these findings, the inventors have developed, in a first major embodiment, a method of treating autoimmune microvascular disease in a subject in need thereof, comprising: Over the years, methods have been developed comprising administering a therapeutically effective amount of diosmin or diosmetin, or a pharmaceutically acceptable salt thereof.

In a second major embodiment, we provide a method of treating ulcers in a subject suffering from an autoimmune microvascular disease, comprising administering to said subject, for a therapeutically effective period, a therapeutically effective amount of A method has been developed comprising administering diosmin or diosmetin, or a pharmaceutically acceptable salt thereof.

In a third major embodiment, we provide a method of treating ulcers in a subject with systemic sclerosis, comprising administering to said subject a therapeutically effective amount of diosmin or A method has been developed that includes administering diosmetine, or a pharmaceutically acceptable salt thereof.

In a fourth major embodiment, we provide a method of treating digital ulcers in a subject with systemic sclerosis, comprising administering to said subject a therapeutically effective amount of diosmin for a therapeutically effective period of time. Alternatively, methods have been developed comprising administering diosmetine, or a pharmaceutically acceptable salt thereof.

Additional aspects and advantages of the invention will be set forth in part in the description that follows and in part will be apparent from the description, or may be learned by practice of the invention. The aspects and advantages thereof will be realized and attained by means of the elements and combinations particularly pointed out in the detailed description and appended claims. It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention as claimed.

DETAILED DESCRIPTION Definitions and Use of Terms Throughout this application, various publications are referenced. The disclosures of these publications are hereby incorporated by reference in their entireties in order to more fully describe the state of the art to which this application pertains. Disclosed references are also individually and specifically incorporated herein by reference for the material contained therein that is discussed in the text on which the reference relies.

When the singular forms “a,” “an,” and “the” or similar terms are used herein, they are understood to include the plural unless the context clearly dictates otherwise. Thus, for example, reference to "an excipient" includes mixtures of two or more such excipients, and the like. As used herein, the word "or" and like terms mean any one member of a particular list and also include any combination of the members of that list.

As used herein, the term "about" or "ca." is accepted in the pharmaceutical industry and due to inherent variability in pharmaceutical products, such as manufacturing variability and product degradation over time. It will compensate for variations such as differences in product strength and bioavailability. This term is used in pharmaceutical practice to consider a product to be pharmaceutically equivalent or bioequivalent to the recited strength of the claimed product, or both where the context requires. allow for any variation that allows it to be evaluated as It is to be understood, of course, that all numerical values expressed herein may be preceded by the term "about."

As used herein and in the claims below, the word "comprise" and its variants "comprising" and "comprises" means "including but not limited to and does not exclude other additives, ingredients, integers, or steps. When an element is described as comprising many components, steps or conditions, that element also includes any combination of such multiples or “consists of” multiples or combinations of components, steps or conditions. or "consisting essentially of".
"Diosmin" is a naturally occurring flavonoid glycoside that can be isolated from various plant sources or obtained from the flavonoid hesperidin. Its molecule has the following chemical structure:

Diosmin has a molecular weight of 608.5 (7-[[6-O-(6-deoxy-α-L-mannopyranosyl)-β-D-glucopyranosyl]oxy]-5-hydroxy-2-(3-hydroxy-4 -methoxyphenyl)-4H-1-benzopyran-4-one).

The molecule is commonly supplied as what is referred to as a micronized purified flavonoid fraction ("MPFF"), and it contains various related compounds, generally at concentrations up to 10%. For purposes of this invention, diosmin refers to the actual diosmin content in the relevant dosage form or method, exclusive of these related compounds.

Diosmetin is the aglycone/active metabolite of diosmin to which diosmin is converted after oral administration and delivery by other routes. Diosmetin has the following chemical structure:

The compound has a molecular weight of 300.266 g/mol and is chemically known as 5,7-dihydroxy-2-(3-hydroxy-4-methoxyphenyl)-4H-1-benzopyran-4-one.
When a range is given by designating the lower limit of a range, or by designating a particular numerical value, separately from the upper limit of that range, separate ranges are defined as any lower variable, upper variable, and specific It should be understood that any combination of numerical values may be defined as mathematically possible. Similarly, when a range is defined as extending from one endpoint to another, it should also be understood to include the distance between the two endpoints excluding the two endpoints.

As used herein, "therapeutically effective amount" refers to an amount sufficient to elicit the desired biological response. The therapeutically effective amount or dose will depend on the patient's age, sex and weight, as well as the patient's current medical condition. Those skilled in the art will be able to determine appropriate dosages depending on these and other factors, in addition to the present disclosure.

"Pharmaceutically acceptable" means pharmaceutical compositions that are generally safe, non-toxic, biologically or otherwise unsuitable, and acceptable for human or veterinary pharmaceutical use, including means useful for preparing a product. "Pharmaceutically acceptable salt" means a salt that is pharmaceutically acceptable as defined above and that possesses the desired pharmacological activity.

When doses of a drug or pharmaceutically acceptable salt thereof are described herein, unless the description states that the doses are based on the weight of the salt, hydrate or solvate, It should be understood that doses are based on the weight of the free base exclusive of any hydrates or solvates thereof.

A "digital ulcer" as used in this application refers to an open wound on the outer surface of the body, most commonly a finger or toe, caused by a non-healing break in the skin.

"Microvessel" refers to blood vessels of the microvasculature, preferably having an average diameter of less than 100 micrometers or 70 micrometers. Similarly, "microvascular disease" refers to a disease that primarily and preferably affects the microvasculature less than about 100 micrometers or 70 micrometers in diameter.

"Autoimmune microvascular disease" refers to a disease affecting systemic microvascular integrity that occurs in the presence of generalized immunodeficiency.

Main Embodiments The present invention is described herein in terms of main embodiments and sub-embodiments. It is to be understood that each sub-embodiment may modify any main embodiment, except where such modifications are logically contradictory or expressly rejected herein. Major embodiments can be combined in any manner, and sub-embodiments can be combined in any manner to further modify any major embodiment, provided that such combinations are logically inconsistent. or except where expressly disclaimed herein.

In a first major embodiment, the present invention provides a method of treating autoimmune microvascular disease in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of diosmin for a therapeutically effective period of time. Alternatively, methods are provided comprising administering diosmetine, or a pharmaceutically acceptable salt thereof.

In a second major embodiment, the present invention provides a method of treating ulcers in a subject suffering from an autoimmune microvascular disease, comprising administering to said subject, for a therapeutically effective period, a therapeutically effective amount of Methods are provided comprising administering diosmin or diosmetin, or a pharmaceutically acceptable salt thereof.

In a third major embodiment, the present invention provides a method of treating ulcers in a subject suffering from systemic sclerosis, wherein said subject is administered a therapeutically effective amount of diosmin or diosmetin for a therapeutically effective period of time. or a pharmaceutically acceptable salt thereof.

In a fourth major embodiment, the present invention provides a method of treating digital ulcers in a subject suffering from systemic sclerosis, comprising treating said subject with a therapeutically effective amount of diosmin or Methods are provided comprising administering diosmetine, or a pharmaceutically acceptable salt thereof.

Sub-embodiments The invention can be further defined in terms of various sub-embodiments. In one subembodiment, the methods of the invention are for treating ulcers in subjects suffering from autoimmune microvascular disease. In another sub-embodiment, the method of the invention is for treating ulcers in a subject suffering from systemic sclerosis. In yet another sub-embodiment, the methods of the invention are for treating digital ulcers in a subject suffering from systemic sclerosis.

In a sub-embodiment, the subject has microangiitis. In another sub-embodiment, the subject has microangiitis in the terminal arterial blood vessels or capillaries. In yet another sub-embodiment, the subject has non-venous microangiitis. In yet another sub-embodiment, the subject has non-venous microangiitis in terminal arterial blood vessels or capillaries.

In one particular sub-embodiment, the methods of the invention are used to treat autoimmune microvascular diseases, and the diseases include rheumatoid arthritis, systemic lupus erythematosus, Sjögren's syndrome, systemic sclerosis, dermatomyositis, mixed connective tissue disease, leukocytoclastic vasculitis, antiphospholipid antibody syndrome, and paraproteinemia, including cryoglobulinemia and cryofibrinogenemia.

The method can also be prescribed based on clinical characterization of affected patients. Thus, in one subembodiment, the subject has a sclerotic condition selected from diffuse systemic sclerosis, localized systemic sclerosis, and localized scleroderma. In another sub-embodiment, the subject has CREST syndrome. In another sub-embodiment, the subject is suffering from digital ischemia and one or more digital ulcers resulting from Raynaud's disease. In yet another sub-embodiment, the subject has one or more digital ulcers due to ischemia due to a combination of microvascular disease and actual capillary loss associated with ischemia due to vasospasm associated with Raynaud's disease. are doing.

The dose employed will depend on the nature and severity of the disease, route of administration, and other factors known to workers of ordinary skill in the art. In one particular embodiment, the therapeutically effective amount is 300-5000 mg of diosmin, or 150-2500 mg of diosmetin, orally administered to a subject daily, preferably divided into two separate doses, or A pharmaceutically acceptable salt thereof. In another specific embodiment, the therapeutically effective amount is 400-2000 mg of diosmin, or 200-1000 mg of diosmetin, orally administered to a subject daily, preferably divided into two separate doses; Alternatively, it is a pharmaceutically acceptable salt thereof. In yet another specific embodiment, the therapeutically effective amount is 800-1200 mg of diosmin or 400-600 mg of diosmetin administered to the subject orally, preferably divided into two separate doses, daily. , or a pharmaceutically acceptable salt thereof.

In any of the above major or sub-embodiments, diosmin or diosmetin is administered to the subject for at least 4 weeks, 8 weeks, 12 weeks, 3 months or 6 months. That is, the duration of therapeutic efficacy is at least 4 weeks, 8 weeks, 12 weeks, 3 months or 6 months.

In any of the above major or sub-embodiments, the subject is an adult 18 years of age or older.

In any of the above embodiments, the method preferably comprises the following treatments:
Prevention of cold exposure Removal of necrotic or infected tissue Management of wound infection Wound cleansing Nutritional support Bandages may be used in conjunction with one or more of these techniques.

In general, the clinical outcomes associated with the use of the treatments of the invention can be broadly classified into two categories: improved wound healing and improved wound care.

Complete wound closure of chronic non-healing ulcers is one of the primary goals and a clinically meaningful endpoint of wound healing. Complete wound closure is defined as skin re-epithelialization without the need for drainage or bandages, confirmed at the clinical site at two consecutive study visits, preferably two weeks apart.

Efficacy of treatment can also be assessed based on facilitated wound closure. Thus, in another sub-embodiment, the treatment provides a clinically meaningful reduction in time to healing using a time versus event analysis (where the event is a complete wound closure).
In a preferred sub-embodiment, the present invention is used for the treatment of ulcers or digital ulcers, and the treatment either completely heals the ulcer or reduces the size of the ulcer relative to placebo. Indicated.

Dosage Form/Route of Administration A pharmaceutical composition for the prophylaxis and/or treatment of a subject, comprising a therapeutically effective amount of diosmin or diosmetin, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable Further provided are pharmaceutical compositions comprising excipients that may be

A "pharmaceutically acceptable" excipient is non-biological or otherwise undesirable, i. The material can be administered to a subject without interacting in a detrimental way with any other component of the composition. The carrier may be chosen to minimize any degradation of the active ingredients and to minimize any adverse side effects in the subject, as is well known to those of skill in the art. Carriers can be solid, liquid, or both.

The compounds of the present disclosure may be administered by any suitable route, preferably in the form of pharmaceutical compositions adapted for such routes, and in doses effective for the treatment or prophylaxis intended. In preferred embodiments, active compounds and compositions may be administered orally or topically.

Suitable carriers and their formulation are published in Remington: The Science and Practice of Pharmacy (19th ed.) ed. A. R. Gennaro, Mack Publishing Company, Easton, Pa., 1995. Oral administration of solid dosage forms can be, for example, discrete units such as hard or soft capsules, pills, cachets, lozenges, or tablets each containing a predetermined amount of at least one compound or composition of the present disclosure. can be presented in In some forms, oral administration can be in powdered or granular form. In some forms, the oral dosage form is sublingual, eg, a lozenge. Compounds of the invention in such solid dosage forms are ordinarily combined with one or more excipients. Such capsules or tablets may contain a sustained release formulation. The dosage form in the case of capsules, tablets, and pills may further comprise buffering agents or may be prepared with enteric coatings.

In some forms, oral administration can be in a liquid dosage form. Liquid dosage forms for oral administration include, for example, pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents (eg, water) commonly used in the art. Such compositions may also comprise adjuvants such as wetting agents, emulsifying agents, suspending agents, flavoring agents (eg sweetening agents) and/or perfuming agents. In some forms, the disclosed compositions may comprise parenteral dosage forms. In other forms, the disclosed compositions may comprise topical dosage forms. Other carrier materials and modes of administration known in the pharmaceutical industry may also be used. The pharmaceutical compositions of the disclosure may be prepared by any of the well-known techniques of pharmacy, such as effective formulations and administration procedures. The above considerations regarding effective formulations and administration procedures are well known in the art and described in standard textbooks. Drug formulations are described, for example, in Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa., 1975; Liberman, et al., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980. and Kibbe, et al., Eds., Handbook of Pharmaceutical Excipients (3.sup.rd Ed.), American Pharmaceutical Association, Washington, 1999.

The disclosed compounds can be used alone or in combination with other therapeutic agents in the treatment or prevention of a variety of symptoms or disease states. Administration of two or more compounds "in combination" means that the two compounds are administered in close enough proximity that the presence of one modifies the biological effect of the other. Two or more compounds can be administered simultaneously, together, or sequentially.

Efforts have been made to ensure accuracy with respect to numbers (eg, amounts, temperature, etc.) in the following tests, but some errors and biases should be accounted for. The following examples are presented to provide those skilled in the art with a complete disclosure and explanation of how to make and appreciate the methods claimed herein, and are purely illustrative of the invention. It is intended to be and is not intended to limit the scope of what the inventors regard as their invention.

Example 1. Diosmin in the Treatment of Digital Ulcers A randomized, double-blind, placebo-controlled clinical trial was conducted to evaluate the effect of diosmin on Raynaud's disease and digital ulcers. In this study, subjects were randomized to receive either 600 mg diosmin twice daily or matching placebo. The test recorded improvement/healing of the ulcer. Subjects with ulcers without ongoing ulcer therapy must have at least one ongoing or worsening digital ulcer for at least one month and are receiving ulcer therapy Subjects must have at least one persistent or worsening ulcer for which therapy has been ongoing for at least 2 months, and therapy must remain ongoing for the duration of the study. there had to be.

The results of this study in ulcer patients are reported in Table 1.

Table 1: Ulcer Response Diagnosis of all digital ulcers (including 9 ulcers in 4 non-scleroderma subjects)

Throughout this application, various publications are referenced, the disclosures of these publications being incorporated by reference into this application in order to more fully describe the state of the art to which this invention pertains. It will be apparent to those skilled in the art that various modifications and variations can be made in this invention without departing from the scope or spirit of this invention. Other embodiments of the invention will be apparent to those skilled in the art from consideration of the specification and practice of the invention disclosed herein. It is intended that the specification and examples be considered as exemplary only, with a true scope and spirit of the invention being indicated by the following claims.

Citation

Claims (15)

1. A pharmaceutical composition for treating digital ulcers in a subject suffering from systemic sclerosis, comprising a therapeutically effective amount of diosmin or diosmetin or a pharmaceutically acceptable salt thereof, wherein said subject is treated with A pharmaceutical composition administered for an effective period of time. 2. The pharmaceutical composition of claim 1, wherein said subject suffers from microangiitis. 3. The pharmaceutical composition of claim 1 or 2, wherein the subject suffers from microangiitis in terminal arterial blood vessels or capillaries. The pharmaceutical composition according to any one of claims 1-3, wherein the subject suffers from non-venous microangiitis. The pharmaceutical composition of any one of claims 1-4, wherein the subject suffers from non-venous microangiitis in terminal arterial blood vessels or capillaries. 6. A subject according to any one of claims 1-5, wherein said subject suffers from a condition of sclerosis selected from diffuse systemic sclerosis, localized systemic sclerosis, and localized scleroderma. pharmaceutical composition of The pharmaceutical composition according to any one of claims 1-6, wherein said subject is suffering from CREST syndrome. The pharmaceutical composition according to any one of claims 1 to 7, wherein said subject suffers from one or more digital ulcers resulting from digital ischemia and secondary Raynaud's phenomenon. said subject suffers from one or more digital ulcers due to ischemia due to a combination of microvascular disease and actual capillary loss with ischemia due to vasospasm associated with secondary Raynaud's phenomenon; A pharmaceutical composition according to any one of claims 1-8. The medicament according to any one of claims 1 to 9, which contains diosmin or a pharmaceutically acceptable salt thereof, has a therapeutically effective amount of 300 to 5000 mg, and is orally administered to the subject every day. Composition. 10. The method according to any one of claims 1 to 9, comprising diosmetin or a pharmaceutically acceptable salt thereof, wherein the therapeutically effective amount is 150-2500 mg and is orally administered to the subject daily. pharmaceutical composition of The medicament according to any one of claims 1 to 9, which contains diosmin or a pharmaceutically acceptable salt thereof, has a therapeutically effective amount of 400 to 2000 mg, and is orally administered to the subject every day. Composition. 10. The method according to any one of claims 1 to 9, comprising diosmetine or a pharmaceutically acceptable salt thereof, wherein the therapeutically effective amount is 200-1000 mg, and is orally administered to the subject daily. pharmaceutical composition of The medicament according to any one of claims 1 to 9, which contains diosmin or a pharmaceutically acceptable salt thereof, has a therapeutically effective amount of 800 to 1200 mg, and is orally administered to the subject every day. Composition. The medicament according to any one of claims 1 to 9, which comprises diosmetine or a pharmaceutically acceptable salt thereof, has a therapeutically effective amount of 400-600 mg, and is orally administered to the subject every day. Composition.